Pulmonary hypertension (PH) is characterized by progressive pulmonary vascular remodeling and perivascular inflammation that contribute to right‑heart failure. Existing approved therapies provide symptomatic and hemodynamic benefit but have limited capacity to reverse established vascular remodeling or restore immune homeostasis, driving interest in new agents that target both metabolic and inflammatory drivers of disease. Liriodendrin (Lidd), a natural compound isolated from Sargentodoxae caulis, has documented anti‑inflammatory and antiproliferative properties in other settings, but its efficacy and molecular targets in PH had not been established.
The authors evaluated Lidd in two commonly used preclinical PH models: the SU5416/hypoxia (SuHx) model in mice and the monocrotaline (MCT) model in rats. In both models, Lidd administration attenuated pulmonary vascular remodeling, reduced perivascular macrophage infiltration, and slowed progression of PH. The source reports these pharmacological effects across the two model systems but does not repeat detailed dosing schedules or numerical effect sizes in this summary; those experimental specifics are available in the original preprint.
To probe cellular mechanisms, primary human pulmonary artery smooth muscle cells (hPASMCs) were treated with Lidd and subjected to RNA‑sequencing. Transcriptomic profiling identified a prominent downregulation of genes and pathways associated with inflammation and cytokine signaling after Lidd exposure, consistent with the observed reductions in perivascular inflammation in vivo.
To determine Lidd’s direct molecular target, the investigators used drug affinity responsive target stability (DARTS) assays combined with western blot validation. These experiments demonstrated that Lidd directly binds PFKFB3, a bifunctional glycolytic regulator that controls fructose‑2,6‑bisphosphate levels and thereby influences glycolytic flux.
Mechanistic studies established that Lidd enhanced the interaction of PFKFB3 with the E3 regulatory factor FZR1. This promoted ubiquitination and degradation of PFKFB3, reducing its cellular abundance. Decreased PFKFB3 levels led to attenuation of glycolysis‑driven lactate production. The chain of events links direct target engagement to changes in cellular metabolism that are relevant to PASMC phenotypic state.
Lower intracellular lactate reduced histone lactylation, an epigenetic modification that the authors show participates in transcriptional activation of proliferative and inflammatory mediators in PASMCs. CUT&Tag sequencing and ChIP‑qPCR were applied to map lactylation‑associated chromatin changes; these assays supported that decreased histone lactylation after Lidd treatment corresponded with reduced transcriptional activation of genes including CCND1, TNC, and CCL2, which are implicated in proliferation and inflammation.
Functionally, Lidd suppressed PASMC phenotypic conversion toward a proliferative and inflammatory state, reducing cell proliferation and migration in vitro and dampening vascular remodeling and macrophage infiltration in vivo. The study also evaluated the role of lactate in this cascade: supplementation with exogenous lactate or manipulations that increase endogenous lactate levels restored histone lactylation. Interestingly, restored lactylation paradoxically potentiated Lidd’s inhibitory effects on PASMC proliferation and migration under some conditions, and these lactate‑mediated effects were dependent on the histone acetyltransferase p300, as p300 inhibition abrogated them.
To confirm target specificity in vivo, the authors used PFKFB3‑deficient murine models. In PFKFB3‑deficient mice, Lidd did not provide additional protection against PH phenotypes, indicating that PFKFB3 is the primary mediator of Lidd’s pharmacological actions in these models.
The preclinical data indicate that Lidd selectively targets the PFKFB3‑mediated glycolytic–epigenetic axis to suppress pulmonary artery smooth muscle cell phenotypic transition, reduce proinflammatory transcriptional programs, and attenuate pulmonary vascular remodeling in two PH animal models. By promoting PFKFB3 ubiquitination and degradation, Lidd lowers glycolysis‑derived lactate and downstream histone lactylation, thereby decreasing transcription of proliferative and inflammatory effectors.
These findings position Lidd as a promising candidate for further preclinical development aimed at reversing vascular remodeling and correcting metabolic–epigenetic drivers of PH. As noted by the authors, this work is reported in a preprint and has not undergone peer review; readers should consult the full preprint for detailed experimental protocols, dosing regimens, quantitative outcomes, and any additional limitations described by the investigators.